1Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
*Corresponding author: Pyoeng Gyun
Choe, Department of Internal Medicine, Seoul National University College of
Medicine, 103 Daehak-Ro, Jongno-Gu, Seoul 03080, Korea, E-mail:
draver@snu.ac.kr
• Received: May 28, 2024 • Revised: July 9, 2024 • Accepted: July 11, 2024
This is an Open-Access article distributed under the terms of the
Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits
unrestricted non-commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
The rise of multidrug-resistant organisms represents a serious global public
health concern. In Korea, the increasing prevalence of carbapenem-resistant
Enterobacterales (CRE) is particularly concerning due to the difficulties
associated with treatment. Data from the Korea Global Antimicrobial Resistance
Surveillance System indicate a yearly increase in CRE cases, with
carbapenemase-producing Enterobacterales being the predominant type. The
capacity of CRE to resist multiple broad-spectrum antibiotics leads to higher
medical costs and mortality rates, underscoring the need for urgent action.
Effective prevention is crucial to curbing CRE outbreaks and transmission.
Antimicrobial stewardship programs (ASPs) play a key role and require commitment
from healthcare professionals to minimize unnecessary antibiotic use, as well as
from policymakers to ensure adherence to ASP guidelines. Given the complexity of
CRE transmission, ASP efforts must be integrated with infection control
strategies for maximum effectiveness. These strategies include adherence to
standard and contact precautions, environmental disinfection, preemptive
isolation, and comprehensive education and training for healthcare personnel.
Additionally, surveillance testing for patients at high risk for CRE and the use
of real-time diagnostic kits can facilitate early detection and reduce further
transmission. Strategies for the prevention of CRE infection should be tailored
to specific healthcare settings. Ongoing research is essential to update and
refine infection control guidelines and effectively prevent CRE outbreaks.
Antibiotics were originally defined as substances produced by microorganisms that
inhibit the growth or proliferation of other microorganisms. This definition has
since been expanded to include artificially synthesized compounds. Since the
discovery of penicillin, the development and use of various antibiotics have
markedly reduced mortality from infectious diseases, positioning antibiotics as
one of the most transformative interventions in modern society. This progress
has led to bold predictions that humanity might one day conquer bacterial
infections. Despite these optimistic projections, bacteria have survived by
employing various mechanisms that nullify the effects of antibiotics. The
resulting resistant bacteria have proliferated, leading to the emergence of
multidrug-resistant organisms (MDROs) that are unresponsive to conventional
treatments. The development of antibiotic resistance is far outpacing the
introduction of new antibiotics [1], and
multiple studies have highlighted the harmful impacts of antibiotic resistance
on socioeconomic and public health indicators, including healthcare costs,
length of hospitalization, and mortality [2,3]. In response, at the 68th
World Health Assembly in 2015, the World Health Organization (WHO) declared
antibiotic resistance a critical threat to human life, calling for international
action plans to address the issue across borders. While antibiotic resistance is
recognized as a key global challenge, Korea exhibits higher antibiotic
prescription rates and antimicrobial resistance than many other countries [4]. The awareness of antibiotic resistance
in Korea has gradually improved, with interventions reducing unnecessary
antibiotic prescriptions; however, resistance rates remain comparatively high,
and some multidrug-resistant bacteria are even on the rise [5]. In particular, the reported incidence of
carbapenem-resistant Enterobacterales (CRE), which is increasing worldwide, is
also gradually climbing in Korea. With limited antibiotic options available for
treating CRE, its increased incidence poses a management challenge, underscoring
the importance of prevention and preemptive strategies.
Objectives
This review provides an overview of the present status of multidrug-resistant
bacteria in Korea, with a focus on CRE. It also explores infection control
strategies for the prevention and preemptive management of CRE infections.
Ethics statement
As this study is a literature review, it does not require institutional review board
approval or individual consent.
Status of multidrug-resistant organisms in Korea
In 2009, Korea enacted the Infectious Disease Control and Prevention Act, which
classified six multidrug-resistant bacterial infections as designated communicable
diseases. These included methicillin-resistant Staphylococcus
aureus (MRSA), vancomycin-resistant S. aureus (VRSA),
vancomycin-resistant enterococci (VRE), multidrug-resistant Pseudomonas
aeruginosa (MRPA), multidrug-resistant Acinetobacter
baumannii (MRAB), and CRE. The Korean government established a sentinel
surveillance system for healthcare-associated infectious diseases, including these
six types of MDROs. In 2017, CRE and VRSA were reclassified as Group 3 infectious
diseases, necessitating continuous surveillance and mandatory reporting. In 2020,
the Infectious Disease Prevention Act was amended, changing the legal classification
system from groups to classes. Consequently, VRSA and CRE were reclassified as Class
2 infectious diseases, and a mandatory surveillance system for these strains has
been maintained to date. MRSA, MRPA, and MRAB are designated as Class 4 infectious
diseases and are monitored through sentinel surveillance.
In May 2016, aligning with the international effort to combat antibiotic resistance,
Korea established the Korea Global Antimicrobial Resistance Surveillance System
(Kor-GLASS). This system was modeled after the Global Antimicrobial Resistance and
Use Surveillance System (GLASS) proposed by the WHO to assess the national status of
antimicrobial-resistant bacteria [6].
Kor-GLASS has been supplemented and adapted to reflect domestic conditions, building
upon the foundation provided by GLASS [6].
Since its inception in 2016, Kor-GLASS has collected data on 12 pathogens, including
Escherichia coli, Klebsiella pneumoniae, S. aureus,
Enterococcus spp., Acinetobacter spp., and P.
aeruginosa. These bacteria are gathered from nine general hospitals
across the nation, with the system confirming antibiotic susceptibility test results
and computing resistance rates.
Based on the annual antibiotic resistance rates among the six key strains from 2016
to 2022, as reported in the Kor-GLASS data (Fig.
1), the resistance rate of S. aureus to methicillin has
been continuously declining since 2016. This trend aligns with observations in other
developed countries [7,8]. To date, no VRSA strains have been identified in Korea.
Suspected strains have been referred to provincial public health and environment
research institutes, as well as the Korea Disease Control and Prevention Agency, for
confirmation. However, all have been identified as vancomycin-intermediate
S. aureus strains [9].
Regarding VRE, carbapenem-resistant P. aeruginosa, and
carbapenem-resistant K. pneumoniae (CRKP), the incidence of
infections caused by resistant bacteria has been rising since the initiation of
sentinel surveillance. This increase coincides with the escalated use of
broad-spectrum antibiotics and mirrors global trends. During the coronavirus disease
2019 pandemic, Korea, like the United States, experienced an uptick in
multidrug-resistant bacterial infections. Several factors may have contributed to
this pattern, including increased antibiotic prescriptions for patients with
respiratory symptoms, the saturation of isolation facilities in medical
institutions, staff shortages, and challenges in adhering to infection control
guidelines due to work overload [10].
Fig. 1.
Rates of antimicrobial resistance for multidrug-resistant pathogens from
2016 to 2020, based on data from the Korea Global Antimicrobial Resistance
Surveillance System (Kor-GLASS). MRSA, methicillin-resistant
Staphylococcus aureus; VREfm, vancomycin-resistant
Enterococcus faecium; CRKP, carbapenem-resistant
Klebsiella pneumoniae; CRPA, carbapenem-resistant
Pseudomonas aeruginosa; CRAB, carbapenem-resistant
Acinetobacter baumannii.
Status of carbapenem-resistant Enterobacterales in Korea
Among the six MDROs, CRE is particularly noteworthy. In 2017, CRE was classified as a
Group 3 infectious disease. Following the revision of the Infectious Disease
Prevention Act in January 2020, CRE was reclassified as a Class 2 infectious
disease. This reclassification mandates that medical personnel report cases within
24 hours in the event of an outbreak or epidemic, as part of a mandatory
surveillance system. The reporting rate of CRKP, which has been collected and
monitored by Kor-GLASS since 2016, has been continuously increasing. Similarly, the
number of reported CRE infections from medical institutions has been rising
annually, with an accelerating growth rate (Fig.
2) [11].
Fig. 2.
Annual numbers of CRE infections from 2018 to 2022 based on a mandatory
surveillance system. CRE, carbapenem-resistant Enterobacterales.
In 2022, K. pneumoniae was identified as the predominant CRE
species, comprising 70.9% of isolated strains, followed by E. coli
(14.0%) and Enterobacter spp. (7.0%). K.
pneumoniae consistently emerged as the most prevalent species
throughout the surveillance period [11]. CRE
can be categorized based on the mechanism of carbapenem resistance.
Carbapenemase-producing Enterobacterales (CPE) produce enzymes that degrade
carbapenems, while non-CPE bacteria demonstrate resistance through other means such
as efflux pumps, changes in outer membrane protein permeability, or overproduction
of AmpC beta-lactamase or extended-spectrum beta-lactamases. In Korea, CPE accounted
for 83.0% of all CRE cases in 2021, surpassing non-CPE pathogens, and this
proportion has been rising. The carbapenemases identified to date include K.
pneumoniae carbapenemase (KPC), New Delhi metallo-beta-lactamase (NDM),
Verona integron-encoded metallo-beta-lactamase (VIM), imipenemase (IMP), and
oxacillinase-48 (OXA-48) [12]. Since 2018,
KPC has been the most common carbapenemase among domestic CPE strains, followed by
NDM and OXA (Fig. 3) [13,14]. The distribution
of carbapenemases varies by region and country, with the transmission of new
carbapenemases being reported in developed countries [15]. Consequently, maintaining up-to-date molecular
epidemiological information on CRE, assessing the domestic context, and performing
continuous monitoring of its spread and outbreaks are crucial.
Fig. 3.
Annual distributions of carbapenemase-producing Enterobacterales from
2018 to 2022. KPC, Klebsiella pneumoniae carbapenemase;
NDM, New Delhi metallo-beta-lactamase; VIM, Verona integron-encoded
metallo-beta-lactamase; IMP, imipenemase; OXA, oxacillinase-48; GES, Guiana
extended-spectrum beta-lactamase.
Interventions to prevent carbapenem-resistant Enterobacterales
transmission
Infection control strategies to prevent the spread of CRE can be organized into three
main components (Fig. 4). Considering the
process that facilitates CRE transmission within hospital settings, the first
component involves selective pressure from antibiotic use, which creates a favorable
environment for CRE to survive and proliferate. The second aspect is the
transmission from CRE-infected or colonized patients to others via the hands of
healthcare workers or medical devices. The third component is the spread of CRE to
the surrounding healthcare environment, where it can form clusters and foster
conditions that promote further transmission. At each stage, adherence to an
antimicrobial stewardship program (ASP) is crucial to combat the survival advantage
of resistant bacteria. Additionally, early screening and isolation of CRE carriers,
contact precautions to prevent transmission, and environmental disinfection to
eradicate colonies can be effective strategies to inhibit the spread of CRE.
Fig. 4.
Conceptual diagram of infection control strategies to prevent the spread
of multidrug-resistant organisms.
Antimicrobial stewardship programs
Since long-term exposure to broad-spectrum antibiotics is a key risk factor for
CRE infection [16,17], adherence to ASPs is essential for reducing the
incidence of MDRO infections [18,19], including CRE. ASPs are interventions
designed to guide medical staff in selecting appropriate antibiotics and using
them for the correct duration. The goal of an ASP is to improve patient safety,
reduce healthcare costs and treatment failures, and limit the emergence of
multidrug-resistant bacteria. Through the ASP, the selective pressure on CRE can
be lessened by curbing the inappropriate use of antibiotics by healthcare
providers. ASPs can be implemented through various practical strategies, such as
limiting excessive antibiotic use through antibiotic approval programs and
establishing clinical guidelines for standardized first-line antibiotic
selection and de-escalation [20].
However, the effectiveness of an ASP is not solely dependent on the
participation and adherence of individual healthcare providers who prescribe
antibiotics. It also relies on the establishment of policies and cultures at
both national and societal levels that enable healthcare providers to engage in
and comply with the ASP [21,22]. For instance, in Korea, measures such
as incorporating ASPs into healthcare accreditation criteria and evaluating fees
for infection prevention and control can act as additional incentives for
healthcare providers to adhere to an ASP [23]. Moreover, as the reporting rate of CRE in long-term care
facilities (LTCFs) is the second highest after general hospitals [11], and CRE colonization in LTCFs is
considered a global risk factor for CRE transmission, it is imperative to
establish an integrated ASP that encompasses various healthcare settings,
including acute care institutions, LTCFs, and primary, secondary, and tertiary
medical institutions. Specific implementation strategies should be tailored to
each hospital context [24].
Contact precautions and hand hygiene
CRE is predominantly transmitted within the hospital setting through direct or
indirect contact with infected individuals or via contaminated surfaces and
environments. Hand hygiene has been recognized as the most effective method for
interrupting this mode of transmission for multidrug-resistant bacteria and
healthcare-associated infections, as evidenced by multiple studies [25,26]. Infection control guidelines consistently advocate for the
implementation of and adherence to standard and contact precautions, which
include hand hygiene, to prevent and manage CRE. These guidelines also encourage
the use of personal protective equipment and the allocation of individual
medical devices for each patient [27].
The WHO guidelines specifically advise that patients colonized or infected with
CRE should be physically separated from those who are not, preferably in
single-room isolation. When this is not feasible, cohorting patients with the
same resistant pathogen is recommended. Additionally, dedicated medical staff
should be assigned to care for these patients to minimize the risk of CRE
transmission [28]. Monitoring hand
hygiene practices is crucial in preventing the spread of CRE and other
multidrug-resistant bacteria. Hospitals must ensure that hand sanitizers and
other necessary resources are readily available to healthcare workers to
facilitate consistent hand hygiene practices [29,30].
Early detection and surveillance testing
Implementing infection control measures, such as preemptive isolation, at an
early stage through CRE surveillance is widely recognized to reduce CRE
infections [31]. Guidelines for the
prevention of healthcare-associated infections, published by the Korean Disease
Prevention and Control Agency, recommend conducting CRE surveillance for groups
at high risk [27]. These groups include
patients transferred from hospitals with a high prevalence of CRE, critically
ill individuals, and those being considered for admission to the intensive care
unit with risk factors such as invasive catheter placement or exposure to
broad-spectrum antibiotics. For these high-risk groups, a screening test is
performed by collecting a stool or rectal swab specimen at the time of
admission. The modified Hodge test is a phenotypic assay initially developed as
a test for CPE. It has been widely used due to its very high selectivity for
KPC-producing CPE—the most common form in Korea—and economical
nature. However, since 2018, it has been excluded from the methods recommended
by the Clinical and Laboratory Standards Institute due to its subjective
interpretation and low sensitivity of around 50% for NDM-producing strains.
Molecular assays, such as polymerase chain reaction, are the most expensive of
the CPE screening methods but have benefits including quick confirmation (within
4 to 6 hours) and high sensitivity. Culture-based test methods have lower
sensitivity than molecular genetic methods and require substantial effort and
time, but they are considered cost-effective [32]. CRE can rapidly spread within healthcare facilities because
resistance genes such as carbapenemases can be horizontally transferred to other
bacteria through plasmids or transposons, and vertical transmission by a single
clone is also possible [33,34]. Therefore, rapid diagnosis and
response are crucial for inhibiting CRE transmission. Furthermore, the
implementation of an ASP requires considerable time to clearly impact the spread
of CRE. Additionally, in the Korean context, limitations on staffing and time
hinder the application of ASPs [35].
Thus, swiftly diagnosing CRE infections through screening tests and subsequently
responding can provide complementary assistance in managing CRE transmission.
Previous studies have similarly confirmed that rapid screening tests can reduce
the incidence of CRE infections [36,37]. To obtain rapid results, methods such
as culturing on chromogenic media (Chromagar KPC, Imipenem-MacConkey method,
etc.) followed by confirmation of CPE genotypes using the Carba NP test or
immunochromatography can be used [38].
Specifically, commercially available early diagnostic kits can simultaneously
detect and differentiate five major carbapenemases— KPC, NDM, OXA-48,
IMP, and VIM, which are common in Korea—within 1 to 2 hours using
automated equipment [39]. However, these
early diagnostic kits can only detect a limited number of enzymes. Furthermore,
for clinical application, an additional systematized approach is required to
utilize the test results for preemptive isolation or promptly switch to
appropriate antibiotics through real-time feedback. Moreover, clearly defined
criteria must be available regarding patient selection for rapid diagnostic
kits, considering costs, human resources, and other factors specific to each
healthcare setting.
Environmental control
The hospital environment can serve as a reservoir for CRE; thus, environmental
disinfection is key to preventing CRE transmission. Per the WHO guidelines, CRE
isolation rooms should undergo additional cleaning and disinfection, with
regular assessments to ensure compliance with environmental cleaning and
disinfection protocols [28]. The US
Centers for Disease Control and Prevention guidance on CRE management highlights
the potential for CRE colonization in sink drains in inpatient rooms.
Consequently, it is critical to clean areas around sinks that are prone to
aerosol generation. After patient discharge, comprehensive room disinfection and
rigorous monitoring are required to confirm that all surfaces have been
adequately disinfected [40]. In short,
rooms that have accommodated patients with CRE infection can become a source of
infection. It is imperative to disinfect all surfaces, with particular attention
to sinks, drains, and faucets, which are recognized as common sites for
bacterial colonization [41].
Additionally, both chlorhexidine gluconate baths and staff-focused infection
control education contribute to reducing the proportion of CRE carriers, despite
their absence from domestic guidelines [42]. Although directly applying recommendations to the Korean
context may pose challenges, it is essential to develop CRE transmission
prevention guidelines that are tailored to the domestic situation, drawing on
local research and evidence.
Conclusion
The ongoing increase in MDROs that are unresponsive to various antibiotics represents
a key global public health challenge. In Korea, the incidence of MDRO infections is
on the rise, mirroring worldwide trends. This pattern has been identified through
the implementation of antibiotic resistance surveillance systems (such as Kor-GLASS)
that adhere to international standards, as well as by monitoring critical
antibiotic-resistant bacteria that are classified as legal infectious diseases.
Thus, continuous surveillance to accurately assess antibiotic resistance is
essential for preventing the spread of MDROs. Kor-GLASS currently excludes primary
and secondary hospitals, LTCFs, and certain regions, indicating a need for
supplementation to establish a comprehensive surveillance system. The establishment
of a national real-time alert system, coupled with data sharing between the
government, acute care hospitals, and LTCFs, is anticipated to provide additional
support in curbing the transmission of MDROs, as observed in other countries.
CRE exhibit resistance to various broad-spectrum antibiotics, including carbapenems,
which leads to high mortality rates due to the limited treatment options available.
Infections caused by CRE not only raise healthcare costs and place a burden on the
healthcare system but also contribute to the spread of healthcare-associated
infections through an increase in pathogen carriers. Prevention is paramount in
curbing the continuous growth of CRE cases. Individual healthcare providers must
adhere to ASPs and minimize unnecessary antibiotic use. Concurrently, robust social
systems must be established to support healthcare providers in complying with ASP
guidelines. Additionally, it is vital to prevent further transmission through
preemptive isolation and surveillance testing of patients at high risk, such as
individuals transferred from LTCFs or admitted to intensive care units. While early
diagnostic kits can be applied for rapid diagnosis, it is advisable to weigh the
advantages and disadvantages of these tests and to use them judiciously, tailored to
the circumstances of each medical institution. Beyond the use of early diagnostic
kits, infection control interventions—including contact isolation, hand
hygiene, environmental cleaning and disinfection, and the education of healthcare
workers—should be implemented in conjunction with ASP practices. Ongoing
research to verify the effectiveness of these infection control strategies in Korea
is essential. Based on the findings, CRE management guidelines suitable for the
domestic situation should be developed to curb CRE infections.
Authors' contributions
Project administration: Choe PG
Conceptualization: Choe PG
Methodology & data curation: Park DH, Choe PG
Funding acquisition: not applicable
Writing – original draft: Park DH
Writing – review & editing: Park DH, Choe PG
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Funding
Not applicable.
Data availability
Not applicable.
Acknowledgments
Not applicable.
Supplementary materials
Not applicable.
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Unresolved policy on the new placement of 2,000 entrants at Korean
medical schools and this issue of Ewha Medical
Journal Sun Huh The Ewha Medical Journal.2024;[Epub] CrossRef
Status of and comprehensive preventive strategies for
multidrug-resistant organisms in Korea: a focus on carbapenem-resistant
Enterobacterales
Fig. 1.
Rates of antimicrobial resistance for multidrug-resistant pathogens from
2016 to 2020, based on data from the Korea Global Antimicrobial Resistance
Surveillance System (Kor-GLASS). MRSA, methicillin-resistant
Staphylococcus aureus; VREfm, vancomycin-resistant
Enterococcus faecium; CRKP, carbapenem-resistant
Klebsiella pneumoniae; CRPA, carbapenem-resistant
Pseudomonas aeruginosa; CRAB, carbapenem-resistant
Acinetobacter baumannii.
Fig. 2.
Annual numbers of CRE infections from 2018 to 2022 based on a mandatory
surveillance system. CRE, carbapenem-resistant Enterobacterales.
Fig. 3.
Annual distributions of carbapenemase-producing Enterobacterales from
2018 to 2022. KPC, Klebsiella pneumoniae carbapenemase;
NDM, New Delhi metallo-beta-lactamase; VIM, Verona integron-encoded
metallo-beta-lactamase; IMP, imipenemase; OXA, oxacillinase-48; GES, Guiana
extended-spectrum beta-lactamase.
Fig. 4.
Conceptual diagram of infection control strategies to prevent the spread
of multidrug-resistant organisms.
Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Status of and comprehensive preventive strategies for
multidrug-resistant organisms in Korea: a focus on carbapenem-resistant
Enterobacterales
